The most convenient method of administering medications to patients is generally to administer the drugs orally. The extent of bioavailability in the same medication may vary from one individual to another, and such difference in the bioavailability is caused by differences in the extent of absorption, metabolism and excretion in human subjects. Changes in bioavailability of the same medication may occur even with the same patient; for example, when the medication is taken together with another medication or foods.
Drug-drug interaction, i.e., when a medication is concurrently administered with another medication, and the in vivo absorption rate of a certain medication changes, has been well known, and the mechanism thereof varies depending on the kind of medications. For example, there are the case that a medication accelerates or inhibits a gastric empting rate, thereby changing the absorption of another medication; the case that a medication has an effect on the medication metabolism in the liver, thereby changing the bioavailability of another medication; and the case that a patent's metabolism exhibits varying rates of the excretion of another medication from the kidney, thereby changing the bioavailability of another medication. (Clinical Pharmacokinetics. Concepts and Applications, M. Rowland and T. N. Tozer, Chapter 17. Drug Interactions., 1980, Lea & Febiger). There are various examples, especially, where the change of medication absorption in human subjects is caused by the change of medication metabolism; therefore, in the preparation procedure of a novel medication, it is required to identify the types of medications which should not be concurrently administered with this medication, according to the drug-drug interaction studies.
As another factor affecting bioavailability, the ingestion of foods has been reported, and the representative example thereof is the change of bioavailability of medications, such as cyclosporine, Ketoconazole and the like, caused by ingestion of a grapefruit juice. From this study, it was found that the medication metabolism is reduced by ingestion of grapefruit juice, whereby the bioavailability of the medication increases. The medication metabolism enzymes involved in such phenomenon in a liver were also identified (G. C. Kane and J. J. Lipsky 2000. Mayo Clin. Proc. 75(9) 933–42).
Generally, food-drug interaction means the change of the bioavailability of medications or drugs caused by intake of foods, and can unintentionally reduce or increase the effect of drug, resulting in therapeutic failure or increased toxicity. This may adversely affect patient care, contribute to morbidity and long treatment time or hospitalization. (L. E. Schmidt and K. Dalhoff, Drugs 2002. 62(10). 1481–1502). For this reason, FDA recommends to test bioequivalency of drug products either under fasted or fed conditions, and for the latter case the meal itself is standardized (Guidance for industry. Food-Effect Bioavailability and Bioequivalence studies).
The mechanism of the food-drug interaction depends on, in addition to the metabolism as mentioned above, physicochemical factors, physiological factors, compositions of foods, compositions of drugs, and combinative factors thereof (D. Fleisher et al., Clin. Pharmacokinetics 1999. Mar. 36(3). 233–254; W. Charman et al., J. Pharm. Sci. 1997. 86(3). 269–282).
The dissolution rate of a medication, being one of innate physicochemical properties of the medication, is an important factor having an effect on the food-drug interaction. When the solubility of a medication significantly depends on a pH of a solution, the dissolution rate varies with the change of pH in a gastrointestinal tract caused by ingestion of foods, whereby the absorption rate of the medication can change.
Indinavir ([1(1S,2R), 5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethylaminocarbonyl)-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D-erytho-pentonamide sulfate (1:1) salt], a drug for treatment of AIDS, is a well known example of a case where the absorption rate of a medication changes in accordance with the change of dissolution rate thereof, and it has been reported that the absorption rate decreases when the drug is administered together with foods. For this reason, this medication should be administered one hour prior to meals or two hours after meals. As a mechanism illustrating how the absorption rate of this medication decreases upon ingestion of foods, it has been known that the dissolution rate of a weakly acidic medication decreases as the pH of gastric fluids rises (P. L. Carver et al., 1999, Pharm. Res. 16(5) 718-).
For tetracycline and fluoroquinoline-based antibiotics, it has been known that the absorption thereof is diminished upon binding with metallic ions contained in foods (M. Garty and A. Hurwitz, 1980 Clin. Pharmacol. Ther. 28. 203–207; G. Hoffken et al. 1988. Rev. Infect. Dis., 10, 138–139). For some of liposoluble medications with very low solubility, the dissolution time increases due to the delay of a stomach emptying time following ingestion of foods, or its solubility in bile upon secretion of the bile increases, whereby the absorption rate of the medication increases (L. E. Schmidt and K. Dalhoff, Drugs 2002. 62(10). 1481–1502).
If the mechanism of the food-drug interaction of a certain medication is found, it may be possible to change the bioavailability thereof by designing its drug formulation to minimize the interaction. For example, in the case that the solubility of medication is a key factor affecting the food-drug interaction, the effect of foods can be minimized by designing the drug formulation which increases the solubility of medication. For example, the crystalline structure of medication may have an effect on the dissolution rate, so that a method has been known of reducing the absorption change caused by foods, by changing the crystalline structure (U.S. Pat. No. 5,294,615).
However, among medications which have a high solubility but are absorbed only at a specific site, especially, in the proximal region of the small intestine, or have a low membrane penetration rate, many medications show a decreased absorption rate upon food ingestion. U.S. Pat. No. 6,338,857 and U.S. Pat. No. 6,368,628 claimed a novel sustained release composition free of food effect. However, these patents do not suggest any mechanism to prevent food effect. Also, in the case of medications which have little room to be improved by the design of novel drug formulation, it has been known that the membrane penetration rate can be improved by altering the molecular structure of the medication itself (Pao et al., Pharm. Res. 1998: 15(2) 221–227).
As mentioned above, even though a plurality of complicated physicochemical, physiological factors have been known regarding the mechanisms of food-drug interaction, it has not been possible to predict the food-drug interaction from the chemical structure or type of a certain medication (B. N. Singh, Clinical Pharmacokinetics 1999. 37:3, 213–255). However, the present inventors first found an interaction between drugs and digestive enzymes, being a novel mechanism of the food-drug interaction, which has never been known in this art.